For the nineteenth and the better part of the twentieth centuries two correlative beliefs were strongly held by almost all neuroscientists and practitioners in the field of neurorehabilitation. The first was that after maturity the adult CNS was hardwired and fixed, and second that in the chronic phase after CNS injury no substantial recovery of function could take place no matter what intervention was employed. However, in the last part of the twentieth century evidence began to accumulate that neither belief was correct. First, in the 1960s and 1970s, in research with primates given a surgical abolition of somatic sensation from a single forelimb, which rendered the extremity useless, it was found that behavioral techniques could convert the limb into an extremity that could be used extensively. Beginning in the late 1980s, the techniques employed with deafferented monkeys were translated into a rehabilitation treatment, termed Constraint Induced Movement therapy or CI therapy, for substantially improving the motor deficit in humans of the upper and lower extremities in the chronic phase after stroke. CI therapy has been applied successfully to other types of damage to the CNS such as traumatic brain injury, cerebral palsy, multiple sclerosis, and spinal cord injury, and it has also been used to improve function in focal hand dystonia and for aphasia after stroke. As this work was proceeding, it was being shown during the 1980s and 1990s that sustained modulation of afferent input could alter the structure of the CNS and that this topographic reorganization could have relevance to the function of the individual. The alteration in these once fundamental beliefs has given rise to important recent developments in neuroscience and neurorehabilitation and holds promise for further increasing our understanding of CNS function and extending the boundaries of what is possible in neurorehabilitation.
Keywords: CI therapy, cortical reorganization, neurorehabilitation, neuroplasticity, stroke, traumatic brain injury, cerebral palsy, multiple sclerosis
Research on Constraint-Induced Movement therapy or CI therapy has demonstrated that the deficit in motor function following damage to the central nervous system (CNS) produced, for example, by stroke can be substantially improved in the chronic phase many years after the injury. Numerous experiments, to be described below, have shown that CI therapy is accompanied by large changes in the function and structure of the brain and that these changes are correlated with the magnitude of the improvement in motor function that the treatment produces. That chronic stroke patients could functionally benefit from rehabilitation, that the mature human brain evinces considerable potential for rewiring and remodeling, and finally that these clinical and neurobiological phenomena are inter-correlated, all contradict firmly held traditional views, as described in the Foreword to this collection of papers.
As noted in the Foreword the first clear example of the capacity of the CNS to change structurally after damage was the seminal discovery of intraspinal axonal sprouting after hemipyramidotomy in monkeys in the mid-1950s by Liu and Chambers (1958). Axonal sprouting was subsequently found to occur in the brain as well as the spinal cord, but it was never clearly shown to be causally associated with changes of importance to the function of an organism. It was generally recognized that axonal sprouting might well have functional relevance, but since a direct demonstration was lacking, general interest in the phenomenon began to wane over time. However, there was a resurgence of interest in the potential of the CNS for neuroplastic change in the last two decades of the twentieth century stimulated by the work of a number of investigators including Kaas, but especially Merzenich. They used single unit recording to demonstrate that the removal of afferent input from a body part in new world monkeys dramatically affects its representation in the brain.
The best known early study involved the removal of input from a primate digit by amputation. The somatosensory cortical representation of the hand area was identified using microelectrode mapping from two to eight months after surgical amputation of either digit 3 only or both digits 2 and 3. In both types of surgery, the cortical representation field of the remaining intact digits expanded to occupy most of the original cortical territory of the now amputated fingers (Merzenich et al., 1984). This study showed that inputs can cross borders of the representation zones of separate digits to “invade” nearby cortical representations, in the dramatic terminology of the Merzenich group. The study also suggested to its authors that the extent of reorganization did not extend beyond 2 mm from the original representational boundary of the digit.
In a striking extension of this work, the Merzenich laboratory demonstrated that not only were cortical representation zones altered by a decrease in afferent input, but the converse was also true. Substantially increased “behaviorally relevant” input from a body part that had to be closely attended to resulted in an increase in the size of its cortical representation, a phenomenon known as use-dependent or skill-related reorganization. In their study (Jenkins et al., 1990), microelectrode maps were obtained of the somatosensory hand representation in cortical area 3b before, immediately after, and three weeks after monkeys underwent somatosensory discrimination training. Some of the monkeys were conditioned to keep the fingertips of one or more of the longest digits of this hand in contact with a grooved rotating disk to receive a reward. The grooved surface of these disks required that monkeys carefully regulate the amount of pressure applied to the disk with their fingertips to maintain contact long enough to be rewarded with a food pellet. The grooved surface also resulted in changes in tactile stimulation when the disk rotated. This “behaviorally relevant” stimulation of the fingers, to which close attention had to be paid in order for hungry monkeys to respond correctly and obtain food reward expanded the cortical representation zones and shifted the representation borders of the digits by a maximum of 2 mm. Other monkeys in the study were conditioned to keep their fingertips in contact with a stationary smooth disk to receive a reward. There was no need to carefully regulate pressure applied with the fingertip to remain in contact so that the task did not require as much attention as the task for the first group of monkeys. The second group of animals did not show cortical reorganization.
The work of Pons et al. (1991) challenged the idea of a 2-mm limit in the amount of reorganization that could occur. Fingers, palm, upper limb, and neck of monkeys were deafferented in the laboratory of one of us (ET) by serial dorsal rhizotomy so that the brain was deprived of inputs from these areas. Tactile evoked responses recorded from the cortex twelve years after the deafferentation indicated that the adjacent area representing the face had invaded the deafferentation zone; that is, the cortical area that had once received input from the deafferented parts of the body now received input from the face whose afferent supply from the periphery remained intact. The expansion of the border of the representation zone of the face greatly exceeded 2 mm. It was observed to take place over the entire representation of the arm (10–14 mm), and was designated “massive” cortical reorganization (Pons et al., 1991). This work aroused the interest of investigators in part because it suggested that plastic brain reorganization could take place over an area large enough to represent an entire arm or leg and thus might be relevant to the rehabilitation of function after brain injury. A portion of the data is shown in Figure 1.
(A) Lateral brain view showing the portion of the postcentral cortex that was deprived of its normal inputs by the deafferentation procedure (“deafferented zone” marked by shading) and the locations of the six parasagittal sections (I...
Even the tenet that new neurons are not produced in the adult mammalian brain (e.g., Rakic, 1985) has come under challenge and been overthrown (reviewed in several articles in this collection of papers). In the early 1990s, Gould et al. published data that confirmed earlier work (Altman and Das, 1965), which was largely ignored, that demonstrated the formation of new neurons, that is, neurogenesis, in the adult rat hippocampus (Gould et al., 1992; Cameron et al., 1993). Two other groups of researchers, at close to the same time, showed that neurogenesis takes place in the olfactory bulb in the adult mammalian brain (Corotto et al., 1994; Lois and Alvarez-Buylla, 1994). As with other forms of plasticity (see above), neurogenesis appears to be experience-dependent: both enriched environments and exercise increase neurogenesis in the hippocampus, and presumably elsewhere (reviewed in van Pragg et al., 2000).
By the middle of the 1990s, the view that the adult brain had substantial capacity for plasticity had gained a strong foothold. CNS reorganization had been shown to occur in adult non-human animals following a variety of interventions, including peripheral nerve section, dorsal root section, digit amputation, sensory input increase, and extensive behavioral training. The concept that the borders between the receptive fields of individual digits were fixed gave way to the idea of borders that were dynamically determined by the amount of sensory input to each receptive field. The importance of the behavioral relevance of changes in sensory input for stimulating plastic changes was also established. Furthermore, investigators showed that the production of new neurons, perhaps the most radical form of plasticity, takes place even in the adult brain.
Human studies: the relevance of cortical reorganization to the functioning of the individual
While these animal studies provided persuasive evidence that the boundaries of cortical representation zones were not fixed and could be altered dramatically by marked changes in afferent input in the mature non-human mammalian brain, this type of cortical reorganization had not yet been demonstrated in humans. Moreover, in all of the animal research it remained possible that the observed changes in cortical representation zones were an epiphenomenon. It was clearly recognized by investigators at that time that there was as yet no compelling evidence indicating that the reorganized cortical representation zones were not just sitting in somatosensory cortex at the top of the brain with no functional significance for the organism.
The occurrence of plastic cortical reorganization in humans was demonstrated in 1994 in upper extremity amputees by two groups using magnetic source imaging, one in San Diego (Yang et al., 1994) and another in Germany (Elbert et al., 1994). The second group, consisting of Elbert, Flor, Taub, and others, continued with a series of studies focused on determining the possible relevance of cortical reorganization to the sensory experience and behavior of humans.
There were major advantages to using human subjects to study the possible functional significance of cortical reorganization. First, humans could speak and report on their sensory experience immediately, while with animals it would take considerable time, often weeks to months, to establish a meaningful system of communication on the basis of conditioned response paradigms to achieve the same result. Moreover, with animals an investigator would have to have a clear idea of what he was looking for to establish a useful method for obtaining specific information through a training program, while with humans important and unexpected information could be obtained from chance remarks that a subject might adventitiously make, especially with respect to unexpected alterations in sensory experiences, as might occur in reporting phantom limb phenomena. A second major methodological advantage of working with human subjects was that they often have long histories of particular types of sensory experiences or performance of specific kinds of behavior which can be easily identified, such as years of carrying out the intensive, repetitive movements involved in practicing a musical instrument. Similarly, because of the existence of health care systems and other social institutions, substantial numbers of humans with particular types of chronic pathology, such as long-term amputees, are potentially available for immediate study. These factors made possible a number of what are, in effect, naturally occurring experiments relevant to the study of the functional significance of cortical reorganization which could be accomplished without requiring extensive or arduous procedures before the experimental measurements could be made.
In an extension of the first study by our group, it was found that the loss of sensory input after upper extremity amputation and the consequent severance of peripheral nerves resulted in massive cortical reorganization that had a very strong direct relationship to the severity of phantom limb pain (PLP) experienced by the amputees in the chronic phase (Flor et al., 1995). The correlation between amount of cortical reorganization and severity of PLP was r = 0.93, which explained almost 85% of the variance in cortical reorganization (Figure 2).
Amount of cortical reorganization (in cm) for each subject plotted against intensity of phantom-limb pain as measured with the Multi-dimensional Pain Inventory. Reprinted from Flor et al. (1995).
Persons with congenital limb aplasia often do not experience PLP or other phantom limb phenomena. In five individuals with congenital limb aplasia and no PLP, neuromagnetic source imaging revealed minimal reorganization of primary somatosensory cortex (SI). Five other individuals who had traumatic amputations after early childhood but who had no PLP also showed minimal reorganization in SI. However, a group of subjects whose amputation occurred in adulthood and did have PLP showed the usual, previously reported cortical reorganization in SI (Flor et al., 1998). In addition, as in the case of the Jenkins et al. monkey study, we found that an increase in sensory input, or an increased reliance on sensory input, led to the converse phenomenon, use-dependent cortical reorganization. For example, magnetic source imaging revealed that string instrument players have an increased (or otherwise changed) cortical representation of the left hand, which performs the complex task of fingering the strings, but not the right hand, which has the less dexterity-demanding task of bowing the strings (Elbert et al., 1995) (see Figure 3). It was further found that blind individuals who employed three fingers on a hand simultaneously to read Braille showed substantial enlargement of the hand area compared to sighted non-Braille-reading persons (Sterr et al., 1998). Additionally, the medial to lateral order of the representations of the three “reading” fingers on the convexity of the cortex was altered or “smeared” in the three-finger Braille readers. This alteration in cortical topography correlated with impaired ability to detect which finger was being touched during tactile threshold determinations; there was no difficulty in determining that one of the fingers had been touched but errors were made in designating which. Control subjects in this experiment were blind individuals who read Braille with one finger. They exhibited an increased representational zone of that finger. However, there was no significant smearing of the representational zones of the digits, nor was there a significant decrease in ability to detect which of the fingers of the hand was being touched during tactile threshold testing. There was thus a strong correlation between the topography of the perceptual disorder and the topography of the altered cortical digital representation zones.
(A) Equivalent current dipoles elicited by stimulation of the thumb (D1) and fifth finger (D5) of the left hand are superimposed onto an MRI (magnetic resonance imaging) reconstruction of the cerebral cortex of a control, who was selected to provide anatomical...
We have also identified a similar phenomenon in terms of motor control of the digits. In focal hand dystonia the individual has difficulty with independently moving two or more digits. It develops most frequently in musicians who often practice their instrument for many hours most days of the week over many years, making repetitive digital movements. For example, an affected pianist might be unable to flex the forth digit to strike a key without at the same time flexing the fifth digit. This problem would, of course, be disabling for musical performance. Magnetic source imaging revealed that there is a smaller distance (fusion) between the representations of the digits in somatosensory cortex for the hands of dystonic musicians than for the hands of non-musician control subjects (Bara-Jimenez et al., 1998; Elbert et al., 1998). This followed up earlier work with animals in the Merzenich laboratory by Byl et al. (1996, 1997) and Wang et al. (1995). In later work, a core area of the auditory cortex was found to be enlarged by a factor of 1.8 in the blind compared with sighted individuals (Elbert et al., 2002). This territorial expansion is consistent with the demonstrated increased ability of the blind to accurately localize acoustic sources in peripheral auditory fields (Muchnik et al., 1991; Lessard et al., 1998; Röder et al., 1999). Blind individuals do not receive more auditory stimulation than sighted individuals. However, to interact effectively with their environment, they have to rely on non-visual, primarily auditory input to a greater extent. There has been considerable other work on cross-modal plasticity in congenitally blind humans. Both auditory (Kujala et al., 1992, 1995a,b, 1997; Alho et al., 1993; Weeks et al., 2000) and tactile (Rösler et al., 1993; Uhl et al., 1993; Kujala et al., 1995a; Röder et al., 1996, 1997; Cohen et al., 1997) stimuli come to be processed in visual cortex. In another study, tinnitus sounds in tonal tinnitus were shown to be related to cortical reorganization in a tonotopic map region in auditory cortex at the dominant frequency of the tinnitus sounds (Mühlnickel et al., 1998). Tinnitus might thus represent a type of auditory phantom phenomenon.
The original stimulus for the work by our group just described above was an experiment by Ramachandran that generated considerable attention. After amputation most patients report spontaneous phantom sensations that seem to emanate from the now-absent body part. It was well known that stimulation of the amputation stump could elicit sensations that were referred to the phantom limb as well as being perceived on the amputation stump (Mitchell, 1871; James, 1887; Cronholm, 1951). In addition, early investigators (Henderson and Smyth, 1948; Cronholm, 1951) and later Ramachandran et al. (1992a,b) reported on upper extremity amputees in whom phantom sensation could also be elicited by tactile stimulation of the face ipsilateral to the amputation. Since the map of the hand on the somatosensory homunculus in the primary somatosensory cortex is flanked by the ipsilateral face laterally and the arm/trunk medially, Ramachandran and coworkers (1992a,b) maintained that this mislocalization of tactile facial stimulation was a direct perceptual correlate of the type of invasion of sensory inputs from these sites into the hand area described in the animal experiments on cortical plastic reorganization by Merzenich et al. (1984) and Pons et al. (1991). Moreover, Ramachandran and coworkers (1992a,b) argued that the phantom sensations arise because in primary somatosensory cortex (SI) somesthetic input from the face area laterally and the upper arm area medially take over the synaptic spaces vacated by degenerating afferent connections in the representational zone of the now missing segment of limb. Ramachandran described subjects who had a precise topographic isomorphism between locations receiving tactile stimulation on the face and the perceived locations of referred sensations on the phantom limb. There was a strict one-to-one relation between a stimulation point on the face and a specific point on the phantom limb. In one subject, this topographic isomorphism was accompanied by some sensory modality specificity; water allowed to wash across the face was perceived as fluid streaming along the phantom limb. The phenomenon was termed facial remapping and was viewed as the basis not only of the mislocalization of tactile stimulation of face and amputation stump to the phantom limb, but of the spontaneous phantom limb experience (Ramachandran and Hirstein, 1998; Ramachandran and Rogers-Ramachandran, 2000). However, as noted above, while Flor et al. (1995) reported a very strong correlation between the magnitude of cortical reorganization in SI and the severity of PLP, the extent of the plastic cortical change in SI was not found to be related to topographically isomorphic remapping or to any other phantom phenomenon including the presence, frequency, length, and intensity of telescoping of the phantom limb (i.e., the progressive shortening of the phantom limb over time). Tactile stimulation of the face gave rise to referred or mislocalized sensation to the phantom limb in 4 of 13 subjects but not in the remaining 9 subjects in the Flor et al. experiment. Moreover, in 3 of the 4 cases it was unrelated to the cortical reorganization in SI, and had precise topographic isomorphism in just one case. Ramachandran reported initially that facial remapping was present in 30–40% of his subjects. However, Knecht et al. (1996, 1998) in a systematic study found no evidence of topographic isomorphism between facial stimulation and phantom experience in any of the eight subjects studied. In follow-up studies, Ramachandran reported that orderly topographic remapping was far less common than observed in his original study; the disparity may have been due to selective referral of cases since his interest in such cases was well-known in the clinical community in his region. Knecht et al. (1996, 1998) found that mislocalization of facial stimulation to the phantom limb in our subjects occurred, but it was not topographically ordered on the phantom nor was it reproducible over time. In addition, topographically imprecise mislocalization of sensory stimulation could be elicited not only from stimulation of the face and ventral chest wall ipsilateral to the amputation stump whose representations border the amputation zone in SI, but almost equally often from the contralateral surface of the face and chest wall, which do not. Moreover, topographically precise facial remapping is apparently a relatively rare phenomenon occurring in less than 7% of the amputee population and is, therefore, of unclear general significance.
The neural basis of phantom limb: the disjunction between phantom limb pain and other phantom limb phenomena
As noted, the type of cortical reorganization associated with PLP is not associated with other phantom limb phenomena. The reason for this puzzling disparity may lie in the results of an experiment performed in the laboratory of Edward Jones in collaboration with one of us (ET) with macaque monkeys that many years earlier had undergone serial section of the sensory roots of all the spinal nerves innervating one of their upper extremities. With immunocytochemical techniques, it was shown that the procedure had different, and in effect opposite, effects on the lemniscal component of the somatosensory system, which transmits tactile and body-position information from the spinal cord and brain stem to processing centers in the brain, and the spinothalamic component of the somatosensory system, which is the major pathway for the transmission of pain information to the brain. In the monkey lemniscal, non-nociceptive system, a loss of cells in the brain stem and thalamic nuclei was observed. In contrast, the activity of thalamic neurons in the central pain pathway increased. A down-regulation of inhibitory γ-aminobutyric acid (GABA) type A receptors in nuclei associated with the central pain system in the thalamus was also detected. With this loss of GABA inhibition, one might expect an increase in pain-related CNS activity.
The amputation of an extremity transects both motor and sensory nerves—transection of the latter resulting in deafferentation. Furthermore, most researchers believe that the phenomenon of central pain, of which the CNS component of PLP would be an example, results from an imbalance of nociceptive and non-nociceptive somatosensory inputs (Casey, 1991). If the neurological consequences of upper extremity amputation in humans are similar to those that accompany somatosensory deafferentation in macaques, then an imbalance in nociceptive and non-nociceptive inputs caused by the increase in activity in spinothalamic pathways may induce or modulate cortical somatosensory reorganization and lead to perturbations that are perceived as PLP. Another possibility is that cortical reorganization driven by the reduction in afferent input after amputation produces or contributes to the imbalance in nociceptive and non-nonciceptive inputs between the spinothalamic and lemniscal circuits. These possible scenarios may explain why the extent of cortical reorganization is related to PLP.
A role for cortical reorganization in PLP is not inconsistent with the extensive evidence that peripheral mechanisms, particularly those involving the amputation stump, also play a role. Indeed, as noted, members of our research group have confirmed the earlier observation of Sherman et al. (1984) of a positive correlation (r = 0.53 in our group's study) between PLP and pain experienced in an amputation stump (Lotze et al., 1999). In conjunction with our results showing cortical reorganization in SI after amputation, this correlation suggests that both central and peripheral processes may interact and contribute to phantom limb pain.
Another experiment from our group suggests the nature of the neural basis of non-painful phantom phenomena (Flor et al., 2000). During tactile stimulation of intact portions of the body in upper extremity amputees, on the occasions when mislocalization of sensation to the phantom limb occurred, it was accompanied by: (1) elevated activity in posterior parietal cortex, which is known to be devoted to elaborating and maintaining a representation of the body and its parts (Stein, 1989; Kew et al., 1994; Bonda et al., 1995), (2) elevated activity in SI, as well as to (3) decreased activity in secondary somatosensory cortex (SII) that might be associated with a disinhibition of the activity in posterior parietal cortex and SI. Thus, non-painful phantom experiences seem to be based on a widely distributed neural network in multiple cortical regions. PLP, however, appears to have a more localized cortical basis in SI.
Nature of the association of cortical reorganization with sensory experience and behavior
The origin of phantom limb phenomena appears to be considerably more complex than envisioned in the Ramachandran hypothesis. However, the hypothesis was both novel and ingenious and it certainly raised the question of the possible relation between cortical reorganization on the one hand, and sensory experience and behavior on the other. Identifying the exact nature of this relationship is important, but underlying this question are the joint issues of the causality and independence of the two phenomena. Modulation of the flow of somatosensory input can produce changes in the representation of the body in primary somatosensory cortex. It is also followed by such changes in perception as the experience of PLP after amputation. Is there a causal relationship between cortical reorganization and PLP so that the two have an invariant relation, or can they be uncoupled from one another? This question is of more than academic interest. As will be described below, cortical reorganization is related to the recovery of function produced by Constraint-Induced (CI) therapy after stroke and other types of damage to the CNS. A question of considerable pragmatic import for CI therapy is whether the observed cortical reorganization is simply an epiphenomenon that occurs as a result of the increased extremity use produced by the therapy, but has no independent status or functional significance; or are the two inextricably related functionally in such a way that altering either one invariably changes the other. If the latter, one could attempt to increase the cortical reorganization associated with CI therapy by some means other than or in addition to the procedures now constituting the treatment, perhaps by pharmacological means, and thereby increase the therapeutic effect. From a practical point of view, the question of the possibility of reciprocal influence is more important than the thornier issue of causality which requires determination of invariant antecedence in time of one process by the other and evaluation of such other factors as possible multiple causation.
In the area of phantom limb phenomena, there are a number of experiments that are relevant to the question of independence and the possibility of mutual influence. Miltner et al. (1999), Taub et al. (1999), Weiss et al. (1999) demonstrated in chronic upper extremity amputees that a Sauerbruch prosthetic limb, which is operated by muscular activity of the amputation stump, eliminated PLP in five of nine subjects and reduced PLP in two other subjects, all of whom reported experiencing PLP prior to wearing the Sauerbruch prosthesis. In contrast, a group of patients who wore a cosmetic prosthesis that did not increase use of the residual limb showed no mean change in amount of PLP. Lotze et al. (1999) also found that each of four upper extremity amputees who made extensive use of a myoelectric prosthesis and had PLP before prosthesis use reported an absence of PLP after long-time use. Seven of eight subjects who either had no prosthesis, a cosmetic prosthesis, or wore myoelectric prostheses for reduced amounts of time reported a continuation of PLP. In addition, fMRI measurements revealed a correlation between cortical reorganization and amount of PLP. It is of additional interest that in another experiment two-point discrimination training on the amputation stump decreased PLP (Flor et al., 2001). The improved sensory discrimination in this study could have been due to the alterations in the cortical map that were demonstrated to occur. The observation that prolonged use of a functional prosthesis dramatically reduces PLP is of therapeutic importance, since otherwise PLP is a relatively treatment-resistant disorder. However, though the two functional prosthesis studies and the stump discrimination training experiment are suggestive, they are not conclusive in demonstrating that cortical reorganization is not an epiphenomenon with respect to PLP. It is possible that manipulation of the amputation stump affected afferent input from neuromas or other structures in the residual limb. For example, Lotze et al. (1999) showed that PLP had a moderate correlation with stump pain (r = −0.53, p < 0.05). Further evidence of the relation of PLP to stump pain is summarized by Sherman (Sherman et al., 1984; Sherman, 1997), though the relationship is moderate rather than strong. It is also possible that manipulation of the stump distracted attention away from perception of pain and it is this rather than the alteration of somatosensory maps in the brain that reduced PLP. The latter consideration is less likely to explain the results from another experiment from our group by Birbaumer et al. (1997). Neuroelectric source imaging was used to assess changes in cortical reorganization in SI after anesthesia of an amputation stump produced by brachial plexus blockade in six PLP patients and four pain-free amputees. Three of six phantom limb subjects in the first group experienced a virtual elimination of current PLP attributable to anesthesia that was mirrored by a very rapid elimination of cortical reorganization in somatosensory cortex. Cortical reorganization remained unchanged in three PLP amputees whose pain was not reduced by brachial plexus blockade and in the phantom pain-free amputation controls though the actual peripheral manipulation was the same in all subjects. Thus, these results show that the cortical reorganization was not simply an epiphenomenon, but instead had a functional relationship to PLP.
While these findings establish a functional link between cortical reorganization and PLP in upper extremity amputees, they do not indicate the direction of that relationship or whether it might be bidirectional. The amputation stump anesthesia greatly reduced afferent input from that portion of the body. This could have eliminated the preexisting cortical reorganization, which in turn eliminated the PLP, or oppositely, the stump anesthesia could have eliminated the PLP, which had the effect of abolishing the cortical reorganization. Alternatively, the peripheral input from the stump may have been independently maintaining both cortical reorganization and PLP. Another possibility is that PLP and cortical reorganization after limb amputation are different manifestations of the same process; they are the same phenomenon that expresses itself with different characteristics in the different domains of CNS activity and subjective experience.
The case for a reciprocal relation between sensory experience and cortical reorganization could be made more strongly by demonstrating that it is possible to affect PLP by altering the somatosensory map through some means other than physically manipulating the amputation stump or reducing afferent input from it. An experiment by Katz and Melzack (1991) and some studies from our group are relevant in this regard (Knecht et al., 1996, 1998; Weiss et al., 2004). Katz and Melzack (1991) showed that transcutaneous electrical nerve stimulation (TENS) of the ipsilateral ear significantly reduced PLP. Since there was no manipulation of the amputation stump, the most plausible way in which this effect could have been achieved would be by affecting the invasion of the amputation zone of the somatosensory map from the neighboring intact face area. Thus, change in phantom pain perception would have been mediated by altering the somatosensory map and could not be explained by manipulating peripheral structures directly associated with the amputation stump. In the area of non-painful phantom sensation, Ramachandran's report of individual cases of topographic facial remapping, while not effectively explaining the phantom limb phenomenon does indicate that phantom sensation can be produced by stimulation of a region of the body not contiguous with the residual limb. The most plausible explanation for this phenomenon is that the reorganization of cortical somatosensory maps following the amputation established new neural connections that could be responsible for the mislocalized sensations. Knecht et al. (1996, 1998) reported routinely producing perceived sensation in the phantom by stimulating the face and ventral chest wall, whose cortical representations border the amputation zone, but rarely locations elsewhere on the body. Care was taken not to stimulate the amputation stump. In perhaps the most telling case, Weiss et al. (2004), using intact human subjects, abolished sensation from the radial and medial three-quarters of the hand by pharmacological blockade of the radial and median nerves. Magnetic source imaging indicated that the cortical representations of the little finger and the skin beneath the lower lip, which are adjacent to opposite sides of the deafferented cortical region, had moved closer together, presumably because of their expansion across the deafferentation zone. Paired-pulse transcranial magnetic stimulation revealed motor cortex disinhibition for two muscles supplied by the unaffected ulnar nerve. In addition, two notable perceptual changes were observed: increased two-point discrimination ability near the lips and mislocalization of touch of the intact ulnar portion of the fourth finger to the neighboring third finger whose nerve supply was blocked and whose cortical representation was invaded by the intact portion of the fourth finger representation. Of particular interest for the present purposes was the immediate improvement in two-point discrimination on the face by abolishing a major portion of sensation of the hand, two locations distant from one another on the body. This is a counterintuitive result that can best be understood as being mediated by changes in the somatosensory maps where they are adjacent to one another.
Summary: the functional significance of cortical reorganization
The line of investigation into the functional significance of cortical reorganization following alterations in afferent input just described can be summarized as follows.
String players with many years of practice on their instruments have an enlarged or otherwise changed cortical representation of the fingers of the hand that has the complex task of fingering the strings, while the opposite hand, which has the less dexterity-demanding task of bowing the strings, does not.
Blind individuals who read Braille with three fingers exhibit a disordered or smeared representation of those three digits. This is correlated with an inability to reliably identify which finger is being touched during tactile threshold determinations.
A similar phenomenon occurs in the motor control of the digits. Musicians with focal hand dystonia who have difficulty making independent movements of individual fingers also show a decreased (fused) representation of the digits in SI.
Blind individuals exhibit a large expansion of a core area in auditory cortex. This is consistent with the increased ability of the blind to localize sounds and their increased reliance on sound to orient in space.
The sounds experienced in tonal tinnitus have been found to be related to cortical reorganization. There was a marked shift of the cortical representation of the tinnitus frequency into an area adjacent to the expected tonotopic location.
The magnitude of cortical reorganization in primary somatosensory cortex (SI) was found to be very strongly correlated with severity of phantom limb pain (PLP).
Congenital amputees and amputees with traumatic amputations when adult who experienced no PLP showed minimal cortical reorganization in SI. Traumatic amputees who reported PLP exhibited massive cortical reorganization in SI correlated in magnitude with the PLP.
A phantom limb phenomenon which is non-painful—mislocalization of sensation to the phantom limb during tactile stimulation of intact portions of the body—was found to be accompanied by elevated activity in posterior parietal cortex, which is known to mediate the perceived location of body parts in space, and in SI, as well as decreased activity in secondary somatosensory cortex (SII).
Prolonged use of a functional prosthesis operated by muscular or myoelectric activity in an upper extremity amputation stump is very strongly correlated with a decrease in PLP, including its frequent elimination. Myoelectric prostheses are also correlated with a reduced amount of cortical reorganization in SI.
Sensory discrimination training on the amputation stump results in a decrease in PLP.
Of particular importance with respect to the nature of the relation of cortical reorganization and sensory experience are the following findings.
Stimulation of the face and ventral chest wall, which are physically distant from the residual limb of upper extremity amputees, but are the source of invasion of the amputation zone in SI, can give rise to sensations mislocalized to the phantom limb. This occurs very rarely in intact individuals.
Anesthesia of an amputation stump by brachial plexus blockade was carried out in six PLP patients. Three of the six subjects with PLP experienced a virtual elimination of the PLP during the blockade while the three others did not. The three patients whose PLP disappeared showed an elimination of cortical reorganization in SI during the brachial plexus blockade while cortical reorganization remained unchanged in the three patients whose PLP was not reduced.
Subjects with intact arms were given a peripheral nerve blockade that abolished sensation from the first three digits of a hand and from the radial portion of the fourth digit. Tactile stimulation of the intact ulnar portion of the fourth digit was frequently mislocalized to the anesthetized third digit. Of even greater interest was the fact that two-point discrimination on the face improved. Both sensory phenomena were correlated with movement of the cortical representations of the face and the intact fifth digit so that they were in closer approximation across the deafferented cortical region.
None of these experiments individually demonstrate conclusively that the alteration of cortical reorganization zones resulting from changes in afferent input has a functional relation to sensory experience or that the two phenomena can mutually influence one another. Individual experiments might be amenable to alternate interpretations. However, the combination of the many experiments involving different experimental manipulations, different domains of experience, and different methods of measurement constitutes a strong body of evidence that the two phenomena, cortical reorganization and sensory experience, can interact with one another in both directions with important consequences for the individual. Each experiment can plausibly be explained by this reciprocal functional relationship. More importantly, it is the weight of the evidence that is important rather than any individual study for giving credence to the close connection between plastic cortical change and change in perception.
Two different kinds of cortical reorganization: input-decrease and input-increase
In the pages above, many examples have been presented indicating the way in which modulating the flow of afferent input is followed by changes in the cortical representation of the body in somatosensory cortex and in other areas of the cortex for other sensory modalities. Loss of sensory input results in an invasion of the deafferentation or amputation cortical zone by innervation from adjacent still-intact portions of the body or by other intact segments of the sensorium. Loss of input may also result in a contraction of cortical representation zones, as occurs after stroke, in both SI and primary motor cortex (MI) representing the affected arm (Liepert et al., 2000) (see below), presumably resulting from the learned nonuse of that extremity. A prolonged increase in behaviorally relevant sensory input leads to an opposite result, an expansion of the cortical representation of the stimulated part of the body. Input-decrease or injury-related cortical reorganization, which is often the result of damage to the CNS (e.g., stroke, blindness) or peripheral structures (e.g., extremity amputation, presumed injury to the cochlea in tinnitus), is often related to consequences that are adverse to the organism, such as PLP, inability to correctly localize the site of tactile stimulation, and nonuse of an affected upper extremity after stroke. However, the effects of input-decrease cortical reorganization can also be positive, such as the increase in two-point discrimination on the face after pharmacological blockade of radial and median nerves in the arm. Input-increase or use-dependent cortical reorganization usually has results that are positive for the individual, such as skill acquisition. The results of neither input-decrease nor input-increase cortical reorganization are inherently adverse or positive for the individual, but in terms of the direction of territorial cortical change, they are phenomenologically opposite. However, the mechanisms involved in the two types of reorganization may be similar. The two processes mentioned most frequently in past discussions of this issue are sprouting from neighboring neural elements and unmasking of previously silent synaptic connections. To these can be added deafferentation hyperexcitability in the case of loss of afferent input, and neurogenesis in the case of input-increase cortical reorganization (Taub et al., 1995; Knecht et al., 1996). The extent to which these, and possibly other as yet unknown, mechanisms contribute to the emergence of input-decrease and input-increase types of cortical reorganization in the adult nervous system and whether these processes are different shortly after intervention and at a later time, are important issues that await resolution by future research.
An interesting example of both types of cortical reorganization taking place concurrently in the same adult nervous system as a result of a single intervention has been described by Elbert et al.(1997). Following upper extremity amputation, magnetic source imaging revealed that tactile stimulation of the lip evoked responses not only in the area of SI corresponding to the face, but also within the cortical area that would normally correspond to the now absent hand. This invasion of the cortical amputation zone in one hemisphere was accompanied by a significant increase in the other hemisphere in the size of the representation of the digits of the intact hand, presumably as a result of an increased importance of sensory stimulation consequent to a greater dependence on that hand because of the loss of the contralateral extremity.
Possible confusion between different types of neural plasticity
In a sense any change occurring in the CNS either as a result of environmental influences, metabolic activity, or the passage of time can be characterized as neural plasticity. These changes can include a large number of processes. A very partial list of them, some of which overlap, would include: learning, increase in afferent input, decrease in afferent input, synaptogenesis, neurogenesis, long term potentiation, other alterations in synaptic strength, Hebbian rewiring, axonal sprouting, increase in the density of dendritic arborization, pruning, various forms of cellular atrophy, and so on. The multiplicity of these processes is a potential source of serious confusion when discussing possible mechanisms of a particular type of experimental outcome. The work that gave rise to the current greatly expanded interest in neuroplasticity came from the Merzenich laboratory. These experiments were discussed originally as cortical reorganization and this usage was followed by the early group of investigators in the field. This term was operationally descriptive of what was being studied. The studies described above all have to do primarily with this phenomenon. Later investigators began referring to this phenomenon in a generic sense as neuroplasticity. Cortical reorganization is certainly an example of neuroplasticity, but it has an as yet not completely known relation to some of the just-cited processes and probably no relation to some of the others. For the sake of clarity and to aid rigorous analysis, it would probably be best to return to the term originally used to describe the processes studied in the experiments described above, cortical reorganization, rather than employing the generally used but potentially confusing generic term “neuroplasticity.”
Prevailing beliefs prior to CI therapy research
Approximately two decades before evidence was beginning to accumulate indicating that, contrary to long-standing belief, the mature mammalian brain is capable of extensive reorganization, another essentially correlative and even more strongly held belief in neurorehabilitation came into serious question. As noted in the Foreword, it was common clinical observation that following stroke or other types of substantial brain damage in humans there was typically a period of slow recovery of function that was usually greatest early after injury and then progressively slowed. At one year after injury patients were routinely observed to have reached a plateau in their motor recovery and only rarely did they exhibit any but the most modest improvement for the rest of their lives (Twitchell, 1951; Bard and Hirschberg, 1965; Parker et al., 1986). Whatever motor function patients had at that point was thought to be close to the maximum that could be achieved no matter what therapeutic intervention was employed. This view was so firmly embedded in clinical belief that it was rarely mentioned in the literature. It was just a given in the field based on general clinical experience.
Animal research: somatosensory deafferentation in monkeys
This belief was brought into question by research with animals, though relevance to the human case was not fully appreciated at first. The matter was clearest in the case of somatosensory deafferentation research with monkeys.
When monkeys are surgically deprived of somatic sensation from a single forelimb by the serial section of dorsal roots, the monkeys do not use that limb again; there is no spontaneous recovery of purposive movement. This was a classic observation in neuroscience (Mott and Sherrington, 1895) that has received multiple replications (Sherrington, 1931; Lassek, 1953; Twitchell, 1954; Knapp et al., 1963). However, in the case of single forelimb deafferentation, it was found that this result could be reversed by the application of two behavioral techniques. If the deafferented limb is trained, especially by the behavioral technique termed shaping, or if the intact limb is given prolonged restraint for approximately one week, the monkeys use the affected extremity purposefully when unrestrained for a variety of purposes (summarized in Taub, 1977, 1980; Taub et al., 1977). The movements are not normal; they are clumsy since somatic sensation is not present to guide fine-grained coordination or to correct errors. However, the movements are very extensive; these include thumb-forefinger prehension (Knapp et al., 1963; Taub and Berman, 1968) and reasonably accurate eye-hand coordination in pointing at a visual target (Taub et al., 1975a). Thus, while the movements are not normal, they are effective. Use of the two behavioral techniques resulted in the conversion of a useless deafferented arm into an extremity that could be used extensively. This clearly constitutes a substantial rehabilitation of movement, though that term was not generally used in connection with animals. Except in the earliest experiments (Knapp et al., 1959, 1963; Taub and Berman, 1963; Taub et al., 1965), each of the animals were in the chronic phase when training began, having had surgery more than six months earlier. Thus, when the same two techniques were later applied to humans after stroke, the results with monkeys suggested that there was no reason not to try working with patients who were also in the chronic phase post-stroke, notwithstanding the traditional wisdom in the rehabilitation field that this would not be productive. If the techniques were to work at all in humans after CNS damage, there did not appear to be any reason why they would not work in the chronic phase after CNS damage as they had in monkeys.
During the course of the past century, several investigators had found that a behavioral technique can be used in animals (Ogden and Franz, 1917; Lashley, 1924; Tower, 1940; Chambers et al., 1972) or humans (Franz et al., 1915; Bach-y-Rita and Bach-y-Rita, 1990; Bach-y-Rita, 1992) to improve motor performance substantially after neurological damage (Ogden and Franz, 1917; Lashley, 1924; Tower, 1940; Chambers et al., 1972). However, in the case of the animal research none of these observations was embedded in a formal theoretical context that allowed the formulation of predictions, nor was the generality of the mechanisms clearly recognized. Consequently, these findings remained a set of disconnected observations. In the case of the human research, the reports were not accompanied by descriptions of explicit protocols that a potentially interested clinician could employ and no clear outcome measures were used. These factors probably resulted in a general lack of attention and discouraged attempts at replication.
Constraint-Induced Movement therapy or CI therapy was the first clearly described and replicable neurorehabilitation technique shown to be capable of producing a substantial improvement in motor function in the chronic phase after stroke and other types of CNS injury. It was derived from the basic behavioral neuroscience research with deafferented monkeys just described. The application of the same techniques used to convert a useless deafferented forelimb to an extremity capable of extensive purposeful movement was based on a conceptual framework that emerged from the primate experiments.
The learned nonuse mechanism was proposed as a means of resolving a central enigma posed by the Mott and Sherrington experiment of 1895 (Mott and Sherrington, 1895). Why did monkeys not use a single deafferented limb? Sherrington's reasonable answer had been that extremity deafferentation interrupted the afferent arm of spinal reflexes, and it was this that abolished use of the extremity even though motor innervation remained intact. Hence the idea emerged that spinal reflexes were the basic building blocks from which behavior was elaborated; it was the fundamental tenet of Sherringtonian reflexology. This was a pervasive view in neurology for the first 70 years of the twentieth century. However, the two simple behavioral techniques noted above enabled very extensive purposive use of a deafferented limb from which all myotatic reflex activity had been abolished. This demonstration and later control experiments showed that the Sherringtonian reflexological explanation of the primate unilateral deafferentation experiments could not be correct. What then could account for the absence of purposive movement after unilateral forelimb deafferentation? The need to address that salient question led to the formulation of the concept of learned nonuse. Several converging lines of evidence suggested that nonuse of a single deafferented forelimb is a learning phenomenon involving a conditioned suppression of movement. The restraint and training techniques appear to be effective because they overcome learned nonuse. The formulation and the evidence for it are described in detail elsewhere (Taub, 1977, 1980; Taub et al., 2006b).
Early attempts to apply the primate deafferentation model to humans after stroke
The initial studies of the application of therapeutic techniques tested in deafferented monkeys to humans were carried out by Ince (1969); Halberstam et al. (1971), and (Ostendorf and Wolf, 1981; Wolf et al., 1989). The first two studies involved the transfer of the simple conditioned response technique used with the deafferented monkeys that Ince had observed in Taub's laboratory (Taub and Berman, 1963; Taub et al., 1965) directly to the rehabilitation of movement of the paretic upper extremity of patients with chronic stroke. The results were positive, but the range of movements trained were limited and consequently, except in a single case, the scope of motor improvement was also limited. This is consistent with what had been observed in the primate deafferentation studies. When only a single conditioned response was trained, motor improvement was limited to that conditioned response. It was only after these two initial attempts at human application were completed that the much greater scope of motor improvement and generalization of training effect produced by the training technique of shaping (Skinner, 1938, 1968) was observed in the primate deafferentation work (Taub et al., 1975a,b).
In 1980, an article was published presenting the learned nonuse formulation and suggesting that on this conceptual basis the same two techniques used to overcome long-standing nonuse of the more-affected limb in chronically deafferentated monkeys could be transferred to humans and might be of value for improving chronic motor deficits after stroke (Taub, 1980). Wolf and co-workers used just one of the two techniques, restraint of the less-affected extremity, to induce remediation of less-affected arm function (Ostendorf and Wolf, 1981; Wolf et al., 1989). Though the effect size was small (d′ = 0.2), it was reliable. There was no report of whether the improvements transferred to the life situation. However, the results appeared promising, especially since training had not been used and there was some question of compliance by some patients with the instruction to wear the restraint device, a sling, for most of waking hours during the intervention period. This type of intervention involving only use of a restraint device is termed Forced Use therapy; it is not CI therapy since it consists of only one of the four primary components of CI therapy (see below).
Demonstration of efficacy of CI therapy at the university of alabama at birmingham (UAB)
Taub et al. (1993, 2006a) employed both the more-affected arm training and contralateral arm restraint portions of the protocol used with deafferented monkeys, and also used a set of behavioral techniques termed the transfer package (Morris et al., 2006; Taub et al., 2006a,b, 2013b). Training of the more-affected arm in the laboratory was carried out using shaping, as was done in the later deafferented monkey studies. This approach, i.e., CI therapy, was applied to the rehabilitation of persons with a chronic upper extremity hemiparesis in two studies (Taub et al., 1993, 2006a) that employed attention-placebo control groups and emphasized transfer of therapeutic gains in the laboratory to the life situation. As noted, patients with chronic stroke were selected as subjects for this study because in the primate deafferentation research, substantial motor rehabilitation was possible well into the chronic phase. In addition, according to the research literature at the time, there was no evidence that any treatment could produce further recovery of function one year after stroke. Therefore, any marked improvement in the motor function of individuals with chronic stroke after an intervention that lasted just two weeks would be of particular therapeutic significance. After a long-standing plateau, the probability would be very low that an abrupt, large improvement in motor ability could be due to spontaneous recovery.
The subjects in the first two experiments in this laboratory were patients with chronic stroke who had experienced CVAs from one to twenty years earlier (mean = 4 years) (Taub et al., 1993, 2006a). Patients were randomly assigned either to an experimental group or a placebo comparison group. The treatment patients received all aspects of the CIMT protocol described below. The control patients were given a placebo procedure. All experimental and control patients had passed a minimum motor criterion before intake into the study (Wolf and Binder-Macleod, 1983); they could be characterized as having a mild/moderate level of deficit. The treatment groups demonstrated a significant increase in motor ability as measured by a laboratory motor test (Wolf Motor Function Test or WMFT) (Wolf et al., 2001; Morris et al., 2001) over the treatment period (p < 0.01); more importantly they showed a very large increase in spontaneous arm use in the life situation over the two-week period as measured by the Motor Activity Log (MAL) (Taub et al., 1993), an instrument with strong clinimetric properties (Uswatte et al., 2005, 2006b). In the larger of the two studies (Taub et al., 2006a), the amount of spontaneous real-world more-affected arm use went from 9% of the amount of use of that extremity compared to before stroke at pre-treatment to 52% at post-treatment, an approximate 5 times increase. The subjects had approximately 80% retention of improved arm use when tested two years after treatment. Thus, the improvement was long-term. The control patients exhibited no change or a decline in arm use over the same period in both experiments.
These results have been confirmed in a large, multisite randomized clinical trial (RCT) in patients 3-9 months after stroke, i.e., the EXCITE trial (Wolf et al., 2006, 2008), and several hundred other smaller studies (Langhorne et al., 2009; Stevenson et al., 2012). Studies that have used attenuated (Butefisch et al., 1995; Foster et al., 1996; Peter and Leidner, 1997; Van der Lee et al., 1999; Dromerick et al., 2000; Charles et al., 2001; Gritsenko et al., 2001; Johnson et al., 2001; Kedlaya et al., 2001; Liepert et al., 2001; Platz et al., 2001) or partial versions (Ince, 1969; Halberstam et al., 1971; Ostendorf and Wolf, 1981; Wolf et al., 1989) of the full protocol have reported positive results but had smaller gains than the two RCTs from our laboratory. The usual missing component was the transfer package (TP, described below). Where our methods were replicated in laboratories set up with the help of and monitored by one of us (ET), the results were very similar (Kunkel et al., 1999; Miltner et al., 1999; Sterr et al., 2002). CI therapy for stroke patients with mild to moderate deficits has now entered clinical practice, with insurance reimbursement provided by a few but not all companies, and is becoming a regular part of the curriculum in physical and occupational therapy academic programs (Morris and Taub, 2010). Consistent with the increasing clinical acceptance of CI therapy, there has been a steady and substantial growth in peer-reviewed publications on CI therapy trials, reviews, and basic neuroscience research over the past 20 years (Figure 4). As of this writing, 523 peer-reviewed papers have been published.
Cumulative growth in peer-reviewed journal articles on CI therapy according to year of publication. Primary-data reports are represented by the “Adult,” “Pediatric” and “Animal” categories. “Secondary”...
Chronicity and age at treatment
The longest delay between CNS insult and treatment in this laboratory/clinic was 50 years; the stroke occurred when the individual was five years old and he was 55 when treated. The magnitude of his improvement was as great as the laboratory average where mean chronicity is 4 years (Taub et al., 2006a). Similar results have been obtained with many patients who received treatment from 20 to 50 years after stroke.
The potential for improvement persists unchanged throughout the lifespan. Several patients have been in their 90s and many have been in their 80s; their treatment effects did not differ in magnitude from individuals in their 20s or teens.
Components of CI therapy
The upper-extremity CI therapy protocol, as currently practiced in the UAB laboratory, consists of four basic components (Taub, 2004; Taub et al., 2006a,b): (1) intensive training of the more-affected arm for multiple days; (2) training with a behavioral technique termed shaping; (3) the transfer package (TP), a set of behavioral techniques designed to facilitate transfer of therapeutic gains from the treatment setting to daily life; and (4) discouraging behaviors that compensate for the nonuse or reduced use of the affected function.
To discourage use of the less-affected arm to compensate for the reduced effectiveness of the more-affected arm after stroke, a padded mitt is worn on the less-affected hand to prevent its use for a target of 90% of waking hours for the entire treatment period. (The target number of hours is less for more-impaired patients who must use an assistive device to walk safely). The amount of time the device is worn is recorded by a timer inserted in the device. A resting hand splint and sling ensemble was used in early experiments. It has been found that restraint of the less-affected arm is the least important component of CI therapy, and can be dispensed with entirely if the training conditions are arranged appropriately (Taub et al., 1999; Sterr and Freivogel, 2003; Ploughman and Corbett, 2004; Uswatte et al., 2006a). For CI Aphasia therapy the use of gestures and nonverbal sounds is strongly discouraged, and for Lower Extremity CI therapy, physical restraint of a body part is also not used.
Shaping is a training method in which a motor or behavioral objective is approached in small steps by “successive approximations” (i.e., a task is gradually made more difficult with respect to a participant's motor capabilities). Its principles were explicitly formulated by Skinner (Skinner, 1938, 1968) and they have been applied to the rehabilitation of movement in this laboratory (Taub et al., 1993, 1994). For rehabilitation, shaping involves providing immediate and very frequent feedback concerning improvements in the quality of movement and frequent encouragement. Further details of the shaping process employed can be found elsewhere (Taub et al., 1994; Taub and Uswatte, 2006; Morris and Taub, 2010).
Pathophysiology and treatment of tinnitus still are fields of intensive research. The neuroscientifically motivated Heidelberg Model of Music Therapy, previously developed by the German Center for Music Therapy Research, Heidelberg, Germany, was applied to explore its effects on individual distress and on brain structures. This therapy is a compact and fast application of nine consecutive 50-min sessions of individualized therapy implemented over 1 week. Clinical improvement and long-term effects over several years have previously been published. However, the underlying neural basis of the therapy's success has not yet been explored. In the current study, the therapy was applied to acute tinnitus patients (TG) and healthy active controls (AC). Non-treated patients were also included as passive controls (PTC). As predicted, the therapeutic intervention led to a significant decrease of tinnitus-related distress in TG compared to PTC. Before and after the study week, high-resolution MRT scans were obtained for each subject. Assessment by repeated measures design for several groups (Two-Way ANOVA) revealed structural gray matter (GM) increase in TG compared to PTC, comprising clusters in precuneus, medial superior frontal areas, and in the auditory cortex. This pattern was further applied as mask for general GM changes as induced by the therapy week. The therapy-like procedure in AC also elicited similar GM increases in precuneus and frontal regions. Comparison between structural effects in TG vs. AC was calculated within the mask for general GM changes to obtain specific effects in tinnitus patients, yielding GM increase in right Heschl's gyrus, right Rolandic operculum, and medial superior frontal regions. In line with recent findings on the crucial role of the auditory cortex in maintaining tinnitus-related distress, a causative relation between the therapy-related GM alterations in auditory areas and the long-lasting therapy effects can be assumed.
Keywords: tinnitus, cerebral reorganization, brain plasticity, auditory cortex, MRI, voxel-based morphometry (VBM), Heidelberg Model of Music Therapy, gray matter
Tinnitus is one of the most common symptoms in ENT medicine (Pilgramm et al., 1999). Whereas short and transient phantom noise seems to be a ubiquitous phenomenon in general population, 5–15% of people are affected by a persisting manifestation, among those, up to 2% of cases being even severely restricted in their quality of life (Axelsson and Ringdahl, 1989; Khedr et al., 2010; Shargorodsky et al., 2010). Beyond that, the phantom noise often carries additional psychiatric, psychosocial, or psychosomatic comorbidities such as anxiety and depression, concentration and attention deficits, as well as sleep disorders (Jacques et al., 2013). This epidemiological profile points to the value of investigating the origins of tinnitus more thoroughly in order to get better understanding of its nature and of the potential for remediation. Tinnitus is thought to be triggered in many cases by cochlear damage, resulting in abnormal or missing afferent input to the auditory cortex (Moller, 2007). However, this specific defect seems not to be sufficient to explain the whole genesis. To date, there are many methods available to explore brain involvement in phantom noise (Galazyuk et al., 2012; Langguth et al., 2013; Noreña and Farley, 2013; Zhang, 2013) including, Transcranial Magnet Stimulation (Theodoroff and Folmer, 2013), Independent Component Analysis of brain potentials (De Ridder et al., 2011b) and morphometric measurements (Schecklmann et al., 2013). Recent neuroimaging studies of tinnitus indicate the involvement of wide-spread brain networks for perception, attention, memory, and emotional aversive processes (Adjamian et al., 2009; Lanting et al., 2009). In this context De Ridder et al. (2013) proposed a neuronal model of phantom perception and its emotional coupling to distress based on a previous model proposed by Jastreboff (1990). According to the authors, missing signals by sensory deafferentation cause high-frequency, gamma band, synchronized neuronal activity in the sensory cortex. This activity only reaches awareness when it co-activates brain networks that are related to self-perception and salience (amygdala, anterior cingulated, anterior insula, and precuneus). In such way getting conscious, the phantom percept also activates a non-specific distress network that in turn overlaps with salience coding, resulting in an emotional coupling of tinnitus to the experience of distress. Structural brain analysis observing neuronal plasticity has been found to be suitable for understanding correlations between such mental sensations and neural mechanisms (Valkanova et al., 2014). Of critical importance are seven studies so far that specifically investigated anatomical deviations in tinnitus (Mühlau et al., 2006; Landgrebe et al., 2009; Schneider et al., 2009; Husain et al., 2011; Leaver et al., 2012; Boyen et al., 2013; Schecklmann et al., 2013). Noteworthy, even though they all consistently report structural differences, their results largely differ regarding both the localization and the direction of changes. However, there is growing consensus on the involvement of gray matter (GM) alterations in auditory brain areas when suffering from tinnitus distress. For instance, Schecklmann et al. (2013) found such an interrelation in the course of a large cross-sectional morphometric study (n = 257), and cross-validated the results in an independent second sample (n = 78). More precisely, tinnitus distress correlated negatively with GM volume in bilateral auditory areas, pointing to higher individual tinnitus distress with lower gray matter volume. Similarly, Schneider et al. (2009) found gray matter loss associated with tinnitus in the Heschl's gyri, again indicating a close relationship between tinnitus and auditory cortices. Leaver et al. (2012) also revealed reduced gray matter next to auditory area in tinnitus patients, and additionally observed a substantial GM decrease in medial frontal cortex (dmPFC). The authors argued that the latter tinnitus-related alterations in dmPFC might not be related to distress, but to individual loudness of tinnitus sensation. Boyen et al. (2013) also observed changes in auditory areas due to tinnitus, but in contrast to the previous findings pointing to an increase of GM.
Suffering from tinnitus does not necessarily mean feeling diseased due to the phantom noise. Quite the contrary, neither perceived loudness nor tinnitus frequency seem to correlate with mental strain, but it is the emotional correlate of tinnitus, that is, tinnitus distress, which may trigger such feelings of diminished well-being (De Ridder et al., 2011a). In line with this assumption, GM alterations in auditory cortex were not correlated with tinnitus sound, but with severity of tinnitus-related distress (Schecklmann et al., 2013). Hence the existence of tinnitus per se (by phantom noise) does not require any therapeutic intervention. But since tinnitus often co-occurs with considerable emotional decline among affected patients, there is still demand for therapeutic assistance. However, many available therapies resulted in relatively small effects or lacked improvement in tinnitus load (Pichora-Fuller et al., 2013).
In case of acute tinnitus manifestation, existing treatment options may be considered unsatisfactory. On the one hand, several pharmacological approaches (Patterson and Balough, 2006) have been established considering tinnitus to be equivalent to sudden sensorineural hearing loss (Hesse and Laubert, 2010) or to any cochlear damage (Shim et al., 2011). However, none of these treatment methods have proven to be effective after replication in controlled trials (Elgoyhen and Langguth, 2011). On the other hand, different types of psychotherapeutic intervention supporting and accompanying medical treatment have also been designed (Schildt et al., 2006; Gerhards and Brehmer, 2010). These adjuvant psychotherapeutic interventions consist of one or more of the following elements: psycho-educative counseling, relaxation training, and general and tinnitus-related stress management. Different approaches designed to manage or to habituate the phantom noise have been established (Tinnitus Retraining Therapy, Cognitive Behavioral Therapy, Progressive Tinnitus Management, Biofeedback, Education, and Relaxation Therapies), partially resulting in persistent therapy success (Herraiz et al., 2007; Hesser et al., 2011; Folmer et al., 2014; Grewal et al., 2014; Myers et al., 2014). Whereas psychological strategies are intended to modulate attention and emotion toward tinnitus, noise maskers and hearing aids instead interact with acoustic sensation to suppress tinnitus perception. Tinnitus sound masking was developed in the early 1970s (Coles et al., 1984) and is still being used in mild cases, because a lasting improvement can be achieved as long as the external noise is applied. The devices led to reduced tinnitus distress, especially when combined with hearing aids amplifying the impaired frequency range (Oz et al., 2013). Direct modulating of the tinnitus-related activity is intended in either Transcranial Direct Current Stimulation (tDCS) or rapid Transcranial Magnet Stimulation (rTMS), too (Langguth and De Ridder, 2013). In most of these studies the primary auditory cortex has been targeted for tinnitus treatment by cortical stimulation (Simon et al., 2012). However, benefits from rTMS therapy have not been shown to persist over time (Theodoroff and Folmer, 2013).
Any effective therapy for tinnitus requires a fundamental understanding of its physiological and neural background. For instance, the “Heidelberg Model of music therapy for Tinnitus” refers to scientific evidence for cerebral circuits of tinnitus enhancement (Argstatter et al., 2008) (for details see Procedure section). This treatment approach strives for an integration of strategies to manage the psychological state and to possibly reverse the underlying neuronal reorganization. For this purpose, complementary music- and psychotherapeutic interventions, comprising emotional regulation of tinnitus load and exercises of frequency discrimination in the spectral range of tinnitus noise, have been organized into several modules, resulting in a manualized short-term music therapeutic treatment concept whose separate treatment modules and long term effects are described in detail by Argstatter et al. (2012). The authors also reported the high clinical efficacy and long-term effects of this approach in chronic tinnitus patients. Corresponding clinical therapeutic effects in patients with acute tinnitus have been previously reported by Grapp et al. (2013). The authors of this study measured a decrease of tinnitus-related mental load in treated compared to untreated patients after 1 week of therapy. This improvement on tinnitus distress by the aforementioned therapy concept formed the starting point of our research. We aimed to investigate the corresponding neural correlates of this distress-related improvement in tinnitus patients more thoroughly. Thus, we sought to gain a deeper insight into the complex brain etiology and into the possibility of cortical reorganization in tinnitus.
Based on previous studies on structural plasticity, we expected a neural correlate of the therapy effect to be most prominent within auditory areas (Heschl's gyri), as tinnitus distress is highly related to structural GM loss in these regions. Whereas micro-structural regeneration processes on a cellular level (Kwok et al., 2011) cannot be directly detected by MRI, corresponding effects on brain tissue (Kleim et al., 2004) seem to be reliably detectable by Voxel Based Morphometry (VBM) (Ashburner and Friston, 2000). By conflating specific evidence for structural changes after therapy (Seminowicz et al., 2013) with assumptions about the rapid intervention-induced expansion of GM as general principle of human neural plasticity (Driemeyer et al., 2008; Taubert et al., 2010; Tavor et al., 2013), we hypothesized a GM alteration also with the Heidelberg Model of Music Therapy after a short-term treatment interval of 1 week.
Methods and participants
In this study, we included participants who were diagnosed with acute tinnitus persisting for a maximum of 3 months, without significant symptom change after an initial medical intervention according to AWMF guidelines (glucocorticoids or rheological drugs). Before including the participants in music therapy, a waiting period up to 4 weeks was warranted in order to prevent both delayed drug response and the influence of possible spontaneous remission. After completion of this pharmacological treatment during the first weeks after tinnitus onset, tinnitus patients underwent a pre-participation evaluation for participation in the music therapy. In addition to standard audiological testing and otolaryngological examination, important demographic and tinnitus-related data were collected. Patients were excluded if the tinnitus was related to anatomic lesions of the ear, to retrocochlear lesions or to cochlear implantation. Further exclusion criteria comprised clinical diagnosis of a co-morbid severe mental disorder, clinical diagnosis of Menière's Disease, severe hyperacusis or severe hearing impairment more than 40 dB beyond the affected tinnitus frequencies. The latter criterion was chosen to exclude interaction between music therapy and hearing aids for the present.
Fifty patients with experience of a recent tinnitus onset (between 6 and 12 weeks prior to the intervention) were invited to participate in the music therapy study subsequent to treatment according to the standard clinical protocol for acute tinnitus in the University Hospital for Ear, Nose, and Throat at the University of Heidelberg. All patients had an age-appropriate hearing level and reported no otological or psychological co-morbidity. At the time point of the pre-participation evaluation (T0) the patients were randomly divided into two groups, a treatment group (TG) and a waiting group for passive tinnitus controls (PTC). The time span between tinnitus onset and T0 was 5.10 (SD 2.14) weeks in TG and 4.63 (SD 2.01) weeks in PTC. For ethical reasons, PTC patients also received the therapeutic intervention, but following the study period. Participants of both groups were instructed about MRI measurements and its noise level. All participants were insured for any health impairment and accidents. They gave written informed consent in accordance with the Declaration of Helsinki. The study was in accordance with the requirements of the ethic review board of Saarland.
After the period of the standard clinical treatment protocol, 7 patients were excluded from music therapy due to disappearance of tinnitus. Two further patients were excluded because of claustrophobia. Thus, the effective sample comprised 19 patients in the TG and 22 patients in the PTC. The patient groups did not differ in age, sex or in level of distress (see Table 1). The mean delay between tinnitus onset and therapy start (T1) was 8.14 (SD 1.85) weeks in TG and 8.10 (SD 1.45) weeks in PTC.
Patient-related as well as tinnitus-related data in an overview.
After recruitment of tinnitus patients, a group of 22 healthy participants were included into the music therapy condition serving as active controls (AC). They were matched in age and sex to the patients' groups. They underwent the same therapy protocol as implemented in TG. This study protocol consisted in 9 consecutive 50-min sessions of individualized therapy over 5 days, comprising acoustic training for frequency discrimination, auditory attention control tasks, and guided exercises for mindfulness and distress regulation.
In total, data from 63 participants from the three groups were included in the analysis. The three samples used for Voxel Based Morphometry (VBM) did not differ in biometric data in sex [χ2(df = 2) = 0.99, p = 0.95] or in age profile [χ2(df = 2) = 1.76, p = 0.42].
Therapy effects on tinnitus severity and individual tinnitus related distress were assessed by Tinnitus Questionnaire (TQ) developed by Goebel and Hiller (1998). The TQ refers to both tinnitus-related functional disabilities (such as concentration difficulties or hearing impairment) and emotional impairments (such as fear, anger or frustration due to tinnitus). TQ scores were obtained at three different times, during inclusion examinations, before start of treatment, and after the therapy week. The preceding TQ assessment as part of the inclusion examination was integrated into the experimental setup to exclude novelty effects from further evaluation of therapy effect.
All participants underwent two MRI sessions on two subsequent weekends. Between these MRI sessions, TG and AC were treated with music therapy according to the Heidelberg Model. Participants of PTC did not receive any intervention during this time. MRI scans were performed at the Department for Neuroradiology in Homburg using a “Skyra” Siemens 3-Tesla-Scanner and a 20-channel head coil. Each MRI session consisted of three parts: functional measurement during a continuous performance task previously used in attention studies (Schneider et al., 2010), high resolution anatomical T1-weighted scan, and functional measurement of emotional processing of tinnitus related (idiosyncratic) and other affective and neutral verbal stimuli (Golm et al., 2013). However, in this paper only the results from the anatomical scans will be reported. The Magnetization Prepaired Rapid Acquisition Gradient Echo (MPRAGE) protocol (Mugler and Brookeman, 1990) was used, resulting in a resolution of 0.9 × 0.9 × 0.9 isometric voxel size covering the whole head.
MRI scans were performed twice, once before (A-image) and one after (B-image) the 1-week period, for the purpose of Voxel Based Morphometry (VBM) (Ashburner and Friston, 2000) as realized for longitudinal measurements by the VBM8-Toolbox (Christian Gaser, University of Jena, http://dbm.neuro.uni-jena.de/vbm). Brain compartments of white and gray matter were segmented, DARTEL normalized by IXI-template to MNI space (Ashburner, 2007), and smoothed by Gaussian kernel of 10 mm radius.
Comparisons of structural changes were calculated by “flexible factorial design” as implemented in SPM8 (Wellcome Trust Centre for Neuroimaging, London, 2010). The numerical procedure was carried out as a Two-Way ANOVA calculating the influence of the three participant groups and the two dependent time points, scanned before and after the study week, respectively. A comparison between treated and untreated patients (TG vs. PTC) was performed to examine differential therapy-induced effects on structural change. Resulting structural findings from this contrast were further used as spatial mask for general effects of music therapy. Specific tinnitus-related therapy effects were calculated by contrast between TG and “treated” AC in conjunction with selected brain clusters from general effects (TG vs. PTC). This step was implemented to separate tinnitus-related effects from general therapy-related effects. All obtained clusters of each comparison were corrected post-hoc by extent threshold of 125 contiguous voxels and reported after family-wise error (FWE) correction on cluster-level of 5% alpha error.
Revealed clusters from GM contrasts between groups were anatomically assigned to brain structures using the cytoarchitectonic maps as published in Morosan et al. (2001) by application of the Anatomy Toolbox (Eickhoff et al., 2006) supplemental to SPM.
Music therapy and assessment of clinical therapy effects
The music therapy according to the Heidelberg Model of Music Therapy for tinnitus (Argstatter et al., 2008) is a manualized short term treatment approach lasting for nine consecutive 50-min sessions of individualized therapy. Therapy takes place over five consecutive days with two therapy sessions per day. The therapy was carried out by a team of two expert therapists, usually one music therapist and one psychotherapist.
Treatment by music therapy was characterized by several distinctive features:
Integration of both active as well as receptive techniques, not passive suppression of the tinnitus sound, but rather self-effective influence on the sounds.
Acoustic attention control by active participation, particularly in the form of vocal exercises both during and between music therapy sessions.
Improvement of acoustic perception by means of detailed training on intonation and listening capacity in the range of the transposed tinnitus frequency.
Musically based training in relaxation and well-being in order to decouple tinnitus from psychophysiological reaction patterns.
Tinnitus counseling using educational techniques focusing on individual tinnitus-related problems.
The treatment modules are described in more detail by Argstatter et al. (2012).
Clinical therapy effect as assessed by TQ
Tinnitus-related mental load in terms of distress or psychiatric disorders was measured by TQ at T0 (pre-participation evaluation), at T1 (therapy start) and therapy end (T2). The resulting therapy effect was assessed by the difference of TQ scores between T1 and T2. Treatment by the compact approach of the Heidelberg Model of Music Therapy over 1 week added up to 450 min of therapy sessions (9 × 50 min). TQ effects between TG and untreated PTC patients were assessed by General Linear Model (df = 1; F = 22.9; MSE = 1374) for repeated measures using SPSS21 (IBM Corp.). The 1-week therapy resulted in a significant (p < 0.00005) effect on change in TQ scores (see Figure 1) between both groups of tinnitus patients: Compared to a slight test-retest effect (about 1.8 TQ scale points) in PTC, in TG a significant (T = −5.7, df = 18, p < 0.0001) decrease of 17.7 (SD 13.6) TQ scale points was measured. In PTC, the TQ score did not significantly change over the observation period of 1 week.
Differences (after minus before) of Tinnitus Questionnaire (TQ) score. Treatment by Heidelberg Model of Music Therapy led to decrease of 16 score points as compared to untreated patients on average (error bars: standard error of mean).
Therapy- related cortical alteration: GM increase in TG vs. PTC
Over the observation period of 1 week, Heidelberg Model of music therapy was applied to TG patients, whereas PTC patients were not treated during this time span. Comparing structural alterations between T1 and T2, several brain regions revealed increased GM density in treated vs. untreated tinnitus patients (see Figure 2), yielding clusters in precuneus, supplemental motor area (SMA), medial superior frontal sulci, prefrontal areas, right Rolandic operculum and right Heschl gyrus (see Table 2). The highest effect was measured in the right Rolandic operculum resulting in GM increase of about 1.7% in treated patients. The resulting contrast was subsequently considered as a mask for general effects of the therapy situation, comprising training tasks, relaxation sessions, and specific auditory exercises.
General structural effects during the therapy week in comparable samples resulted in widely spread increased GM density in TG vs. PTC over 1 week (p < 0.001 uncorrected, 125 voxels extent threshold). Clusters in precuneus, medial superior frontal...
Clusters showing increase of gray matter density in TG vs. PTC over 1 week.
Cortical alterations in “treated” AC vs. untreated PTC
In “treated” AC, an increase of GM density also occurred in precuneus and medial superior frontal areas (see Figure 3) when contrasted with untreated PTC. This result overlapped with clusters revealed by contrast between TG and PTC. However, the contrast in AC did not reach the magnitude of the effect as observed in TG (see Table 3). No Clusters in temporal areas were observed.
Over the study week, clusters with increased GM density also were observed comparing AC vs. PTC in precuneus and frontal lobe (p < 0.001 uncorrected, 125 voxels extent threshold).
Clusters representing increased gray matter density in AC vs. PTC over 1 week.
Tinnitus-specific GM alterations: contrast between TG vs. AC
Comparison of TG and AC each with experience of the therapy week, respectively, but different in tinnitus presence, was performed to assess specific tinnitus-related structural effects due to the therapeutic intervention. This contrast was calculated within the clusters from general effects of the music therapy as calculated by contrast between TG and untreated PTC. Thus, this calculation is regarded as a selection of tinnitus-related effects within therapy-related structural GM alterations. Figure 4 shows the resulting clusters in right auditory and medial superior frontal areas, covering the right Heschl gyrus and the right Rolandic operculum (see Table 4).
Tinnitus-related alterations by comparison between TG and AC, each with experience of music therapy, were separated within the therapy-related alterations as measured by the contrast between TG and PTC (p < 0.001 uncorrected, 125 voxels extent...
Separation of tinnitus-related from therapy-related GM alteration (*p < 0.05 after FWE correction) by calculating contrast TG > AC within mask of general therapy effect (TG > PTC).
The present study was very innovative due to the homogeneity of patient samples. Most of previous studies on neural correlates of tinnitus distress have been carried out on patients with chronic tinnitus in which tinnitus duration was not taken into account. Importantly, in this paper, these potentially moderating effects of tinnitus duration were explicitly controlled for by including only patients with a recent onset of tinnitus persisting for a maximum of 3 months. On the whole, only a few studies so far have engaged in systematic measurements of such neural alterations in acute tinnitus. Among them, Job et al. (2012) found neural hyperactivities in attention and emotion related areas especially in the insula, the ACC and the PFC in military adults with acute acoustic trauma and consequent tinnitus. In addition, Vanneste et al. (2011) examined the differences of the neural network between tinnitus of recent onset and chronic tinnitus. Their results indicate that the neural structures detected in both acute and chronic tinnitus were identical (comprising auditory cortices, insula, dorsal ACC and premotor cortex) but they also revealed different activity and connectivity patterns within this network.
In line with the previous findings of Argstatter et al. (2012) as well as of Grapp et al. (2013), a significant clinical improvement by the Heidelberg Model of music therapy was quantified using TQ. Thus, the neuro-music therapy approach according to the “Heidelberg Model” seems to provide an effective treatment option for patients with acute tinnitus if initial medical treatment fails to induce remediation. In these studies, both a significant improvement in subjectively perceived tinnitus distress and GM changes were evident immediately after the treatment. The improvements in tinnitus distress not only concerned the patients' cognitive and emotional strategies dealing with tinnitus, but also its intrusiveness and subsequent auditory perception difficulties. Compared to most other therapy options for tinnitus patients, the Heidelberg Model of Music Therapy goes far beyond a pure symptom management. At the core of this treatment approach, the patients are “confronted” actively with their individual tinnitus sounds and are instructed to deal with their tinnitus explicitly instead of trying to ignore them.
In the present study, results revealed that, consistent with the clinical effects of music therapy, GM increased substantially in treated patients (TG) as well as in active controls (AC) compared to untreated patients (PTC). Both TG and AC experienced the same exercises and therapeutic sessions. However, GM increase in treated patients covered more brain areas and yielded higher effect sizes compared to the AC. One may speculate on these findings that healthy controls did not similarly profit from the therapeutic interventions as did tinnitus patients. While tinnitus distress is treated both by relaxation techniques and by frequency discrimination exercises, healthy subjects probably experienced these approaches as “mental wellness” only due to their general influence on the distress network (De Ridder et al., 2013). This may contribute to explain the different effect sizes despite equal training schedule. However, this difference was expected due to a specificity of therapeutic effects on patients suffering from tinnitus (compensation view).
The tinnitus-related structural effects, or the therapy-induced GM alterations, respectively, could be consistently located on areas that are considered to be most sensitive for tinnitus-related distress (Leaver et al., 2012; De Ridder et al., 2013; Schecklmann et al., 2013). However, findings on the direction of the structural therapy effects revealed in our study were not in line with previous findings on tinnitus distress: Whereas mental tinnitus load had been previously associated with GM loss in Heschl's gyri and in dorsomedial frontal location, improvement by music therapy intervention resulted instead in GM increase in these areas.
Most probably music therapy was able to influence and reinforce auditory sensation of those frequencies that were disrupted by a partial hearing impairment. Many patients reported a variability of tinnitus pitch in the course of therapy sessions and lower tinnitus loudness after the therapy week (Hutter et al., 2014). As this partial hearing loss is considered to cause the phantom noise (Lanting et al., 2009), exercises of frequency discrimination in the spectral range of tinnitus might be involved in the reduction of distress and loudness. Although a rapid direct cochlear regeneration can be deemed implausible, further compensation strategies using overtone or envelope characteristics of musical harmonics can be trained to enhance signal extraction for auditory processing. A higher perceptual efficiency regarding the defective frequencies is then able to more activate those areas within auditory cortex that formerly sustained a loss of GM due to lack of signal. More neuronal activation in turn modulates reconstruction processes in the neuronal network, for example, by a down regulation of restrictive factors for neuronal contact in the peri-neuronal net (Wang and Fawcett, 2012). Although VBM is not able to directly depict cellular activity, one may assume that these regeneration processes are similar to re-innervation mechanisms, involving the peri-neuronal net proteins (Kwok et al., 2011). Results from training studies in a mouse model indicate a subsequent growth of synaptic bulk accompanied by a dilatation of the neuronal network on tissue level over several days (Kleim et al., 2004). On a macroscopic level, this tissue augmentation can be detected as a rapid increase of GM density by structural MRI (Warraich and Kleim, 2010). Driemeyer et al. (2008) also underlined these temporal dynamics of structural plasticity by training in humans. They observed a major increase of GM as early as after 7 days during a continuous motor coordination training task. Recent studies even report a reduction of training-induced cortical reorganization despite ongoing exercises over longer observation times (Tennant et al., 2012). This also may explain our results of striking GM alterations due to the compact therapy over 1 week.
In contrast to bilateral results of Schecklmann et al. (2013), the music therapy influenced the right auditory areas only at the reported statistical level. This lateralization may be based on functional lateralization in auditory processing (Warrier et al., 2009), indicating that the right Heschl's gyrus might be more involved in spectral-related acoustic information. In general, the left primary auditory cortex is more active in right-handed subjects, but it shows more sensitivity to temporal stimulus variation compared to frequency variation (Izumi et al., 2011). However, a frequency discrimination task requires more involvement from the right auditory cortex (Doeller et al., 2003). Thus, the Heidelberg Model of music therapy comprising exercises of frequency discrimination in the impaired spectral range was able to specifically repair the tinnitus-related GM loss in the right Heschl's gyrus.
Limitations of the study should be discussed. The TQ scores of included tinnitus patients ranged from 7 to 67 with an average score of 37.3 ± 16. This value corresponds to mild or middle tinnitus-related distress. Further, only patients with general hearing impairment less than 40 dB were included for the present. Therefore, therapy success in severe cases cannot be predicted by this study.
Another limitation generally concerns the measurement of gray matter alterations by SPM and VBM. Due to usage of non-linear deformation, there is some residual impreciseness during the overlap of gyri and sulci between individual brains. Although we calculated with repeated intra-subject measures, the assignment of individual contrasts to the standard space must be critically regarded. The relative quality of the DARTEL normalization used in the study has been compared with several other methods by Klein et al. (2009), resulting in an acceptable rating.
Further limitations are related to possible interpretations of VBM contrasts indicating a shifted probability of focal GM or WM proportion. It is hard to decide whether its origin may be found in some growth within certain brain structures or slightly shifted segmentation results due to certain tissue alteration.
The Heidelberg Model of Music Therapy was able to reveal both rapid clinical improvements related to tinnitus distress and evidence of this specific therapeutic effect on brain areas suspected to play a role in sustaining tinnitus-related distress. When taking into account that the Heidelberg Model of Music Therapy has been shown to provide long-lasting effects (Argstatter et al., 2012), the observed structural brain plasticity can be assumed to be causative. Due to the rapid intervention in acute tinnitus this therapy may be able to prevent tinnitus from chronification (Grapp et al., 2013).
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Financial support: The study was supported by KTS Klaus Tschira Stiftung gGmbH. Many thanks to Sandra Dörrenbächer and Dr. Carrie Ankerstein for stylistic and linguistic improvement of this paper.
- Adjamian P., Sereda M., Hall D. A. (2009). The mechanisms of tinnitus: perspectives from human functional neuroimaging. Hear Res. 253, 15–31. 10.1016/j.heares.2009.04.001 [PubMed][Cross Ref]
- Argstatter H., Grapp M., Hutter E., Plinkert P., Bolay H. V. (2012). Long-term effects of the “Heidelberg Model of Music Therapy” in patients with chronic tinnitus. Int. J. Clin. Exp. Med. 5, 73–288. [PMC free article][PubMed]
- Argstatter H., Krick C., Bolay H. V. (2008). Music therapy in chronic tonal tinnitus. Heidelberg model of evidence-based music therapy. HNO56, 678–685. 10.1007/s00106-008-1722-1 [PubMed][Cross Ref]
- Ashburner J. (2007). A fast diffeomorphic image registration algorithm. Neuroimage38, 95–113. 10.1016/j.neuroimage.2007.07.007 [PubMed][Cross Ref]
- Ashburner J., Friston K. J. (2000). Voxel-based morphometry—the methods. Neuroimage11, 805–821. 10.1006/nimg.2000.0582 [PubMed][Cross Ref]
- Axelsson A., Ringdahl A. (1989). Tinnitus—a study of its prevalence and characteristics. Br. J. Audiol. 23, 53–62. 10.3109/03005368909077819 [PubMed][Cross Ref]
- Boyen K., Langers D. R., de Kleine E., van Dijk P. (2013). Gray matter in the brain: differences associated with tinnitus and hearing loss. Hear Res. 295, 67–78. 10.1016/j.heares.2012.02.010 [PubMed][Cross Ref]
- Coles R. R. A., Baskill J. L., Sheldrake J. B. (1984). Measurement and management of tinnitus. J. Laryngol. Otol. 98, 1171–1176. 10.1017/S0022215100148248 [PubMed][Cross Ref]
- De Ridder D., Elgoyhen A. B., Romo R., Langguth B. (2011a). Phantom percepts: tinnitus and pain as persisting aversive memory networks. Proc. Natl. Acad. Sci. U.S.A. 108, 8075–8080. 10.1073/pnas.1018466108 [PMC free article][PubMed][Cross Ref]
- De Ridder D., Vanneste S., Congedo M. (2011b). The distressed brain: a group blind source separation analysis on tinnitus. PLoS ONE6:e24273. 10.1371/journal.pone.0024273 [PMC free article][PubMed][Cross Ref]
- De Ridder D., Vanneste S., Weisz N., Londero A., Schlee W., Elgoyhen A. B., et al. . (2013). An integrative model of auditory phantom perception: tinnitus as a unified percept of interacting separable subnetworks. Neurosci. Biobehav. Rev. 44C, 16–32. 10.1016/j.neubiorev.2013.03.021 [PubMed][Cross Ref]
- Doeller C. F., Opitz B., Mecklinger A., Krick C., Reith W., Schröger E. (2003). Prefrontal cortex involvement in preattentive auditory deviance detection: neuroimaging and electrophysiological evidence. Neuroimage20, 1270–1282. 10.1016/S1053-8119(03)00389-6 [PubMed][Cross Ref]
- Driemeyer J., Boyke J., Gaser C., Büchel C., May A. (2008). Changes in gray matter induced by learning–revisited. PLoS ONE3:e2669. 10.1371/journal.pone.0002669 [PMC free article][PubMed][Cross Ref]
- Eickhoff S. B., Heim S., Zilles K., Amunts K. (2006). Testing anatomically specified hypotheses in functional imaging using cytoarchitectonic maps. Neuroimage32, 570–582. 10.1016/j.neuroimage.2006.04.204 [PubMed][Cross Ref]
- Elgoyhen A. B., Langguth B. (2011). Pharmacological approaches to tinnitus treatment, in Textbook of Tinnitus, eds Moller A. R., Langguth B., DeRidder D., Kleinjung T., editors. (New York; Heidelberg; London: Springer; ), 625–638.
- Folmer R. L., Theodoroff S. M., Martin W. H., Shi Y. (2014). Experimental, controversial, and futuristic treatments for chronic tinnitus. J. Am. Acad. Audiol. 25, 106–125. 10.3766/jaaa.25.1.7 [PubMed][Cross Ref]
- Galazyuk A. V., Wenstrup J. J., Hamid M. A. (2012). Tinnitus and underlying brain mechanisms. Curr. Opin. Otolaryngol. Head Neck Surg. 20, 409–415. 10.1097/MOO.0b013e3283577b81 [PMC free article][PubMed][Cross Ref]
- Gerhards F., Brehmer D. (2010). Ablenkungs- und Entspannungstraining bei akutem tinnitus. Effekte einer Ergänzung HNO-ärztlicher Behandlung. HNO58, 488–496. 10.1007/s00106-009-2019-8 [PubMed][Cross Ref]
- Goebel G., Hiller W. (1998). Tinnitus-Fragebogen: (TF); ein Instrument zur Erfassung von Belastung und Schweregrad bei Tinnitus; Handanweisung. Göttingen: Hogrefe Verl. für Psychologie.
- Golm D., Schmidt-Samoa C., Dechent P., Kröner-Herwig B. (2013). Neural correlates of tinnitus related distress: an fMRI-study. Hear Res. 295, 87–99. 10.1016/j.heares.2012.03.003 [PubMed][Cross Ref]
- Grapp M., Hutter E., Argstatter H., Plinkert P. K., Bolay H. V. (2013). Music therapy as an early intervention to prevent chronification of tinnitus. Int. J. Clin. Exp. Med. 6, 589–593. [PMC free article][PubMed]
- Grewal R., Spielmann P. M., Jones S. E., Hussain S. S. (2014). Clinical efficacy of tinnitus retraining therapy and cognitive behavioural therapy in the treatment of subjective tinnitus: a systematic review. J. Laryngol. Otol. 128, 1028–1033. 10.1017/S0022215114002849 [PubMed][Cross Ref]
- Herraiz C., Hernandez F. J., Toledano A., Aparicio J. M. (2007). Tinnitus retraining therapy: prognosis factors. Am. J. Otolaryngol. 28, 225–229. 10.1016/j.amjoto.2006.09.004 [PubMed][Cross Ref]
- Hesse G., Laubert A. (2010). Zur pharmakotherapie des akuten und chronischen tinnitus. HNO10, 990–998. 10.1007/s00106-010-2179-6 [PubMed][Cross Ref]
- Hesser H., Weise C., Westin V. Z., Andersson G. (2011). A systematic review and meta-analysis of randomized controlled trials of cognitive-behavioral therapy for tinnitus distress. Clin. Psychol. Rev. 31, 545–553. 10.1016/j.cpr.2010.12.006 [PubMed][Cross Ref]
- Husain F. T., Medina R. E., Davis C. W., Szymko-Bennett Y., Simonyan K., Pajor N. M., et al. . (2011). Neuroanatomical changes due to hearing loss and chronic tinnitus: a combined VBM and DTI study. Brain Res. 1369, 74–88. 10.1016/j.brainres.2010.10.095 [PMC free article][PubMed][Cross Ref]
- Hutter E., Grapp M., Argstatter H., Bolay H. V. (2014). Music therapy for chronic tinnitus: variability of tinnitus pitch in the course of therapy. J. Am. Acad. Audiol. 25, 335–342. 10.3766/jaaa.25.4.5 [PubMed][Cross Ref]
- Izumi S., Itoh K., Matsuzawa H., Takahashi S., Kwee I. L., Nakada T. (2011). Functional asymmetry in primary auditory cortex for processing musical sounds: temporal pattern analysis of fMRI time series. Neuroreport22, 470–473. 10.1097/WNR.0b013e3283475828 [PubMed][Cross Ref]
- Jacques D., Nozeret Y., Zdanowicz N., Reynaert C., Garin P., Gilain C. (2013). Tinnitus and psychiatric comorbidities in liaison psychiatry analysis of three years in an audiophonology centre. Psychiatr. Danub. 25 (Suppl. 2), S102–S104. [PubMed]
- Jastreboff P. J. (1990). Phantom auditory perception (tinnitus): mechanisms of generation and perception. Neurosci. Res. 8, 221–254. 10.1016/0168-0102(90)90031-9 [PubMed][Cross Ref]
- Job A., Pons Y., Lamalle L., Jaillard A., Buck K., Segebarth C., et al. . (2012). Abnormal cortical sensorimotor activity during “Target” sound detection in subjects with acute acoustic trauma sequelae: an fMRI study. Brain Behav. 2, 187–199. 10.1002/brb3.21 [PMC free article][PubMed][Cross Ref]
- Khedr E. M., Ahmed M. A., Shawky O. A., Mohamed E. S., El Attar G. S., Mohammad K. A. (2010). Epidemiological study of chronic tinnitus in Assiut, Egypt. Neuroepidemiology35, 45–52. 10.1159/000306630 [PubMed][Cross Ref]
- Kleim J. A., Hogg T. M., VandenBerg P. M., Cooper N. R., Bruneau R., Remple M. (2004). Cortical synaptogenesis and motor map reorganization occur during late, but not early, phase of motor skill learning. J. Neurosci. 24, 628–633. 10.1523/JNEUROSCI.3440-03.2004 [PubMed][Cross Ref]
- Klein A., Andersson J., Ardekani B. A., Ashburner J., Avants B., Chiang M. C., et al. . (2009). Evaluation of 14 nonlinear deformation algorithms applied to human brain MRI registration. Neuroimage46, 786–802. 10.1016/j.neuroimage.2008.12.037 [PMC free article][PubMed][Cross Ref]
- Kwok J. C., Dick G., Wang D., Fawcett J. W. (2011). Extracellular matrix and perineuronal nets in CNS repair. Dev. Neurobiol. 71, 1073–1089. 10.1002/dneu.20974 [PubMed][Cross Ref]
- Landgrebe M., Langguth B., Rosengarth K., Braun S., Koch A., Kleinjung T., et al. . (2009). Structural brain changes in tinnitus: grey matter decrease in auditory and non-auditory brain areas. Neuroimage46, 213–218. 10.1016/j.neuroimage.2009.01.069 [PubMed][Cross Ref]
- Langguth B., De Ridder D. (2013). Tinnitus: therapeutic use of superficial brain stimulation. Handb. Clin. Neurol. 116, 441–467. 10.1016/B978-0-444-53497-2.00036-X [PubMed][Cross Ref]
- Langguth B., Kreuzer P. M., Kleinjung T., De Ridder D. (2013). Tinnitus: causes and clinical management. Lancet Neurol. 12, 920–930. 10.1016/S1474-4422(13)70160-1 [PubMed][Cross Ref]
- Lanting C. P., de Kleine E., van Dijk P. (2009). Neural activity underlying tinnitus generation: results from PET and fMRI. Hear Res. 255, 1–13. 10.1016/j.heares.2009.06.009 [PubMed]